The mounting of an antibody response depends on B cells moving within lymphoid organs to sites where they can encounter antigen, relocalizing to interact with helper T cells and later moving to specialized niches that support plasma cell and germinal center cell differentiation. Epstein Barr Virus-Induced gene-2 (EBI2 or GPR183) guides activated B cells to inter- and outer- follicular regions, prior to their differentiation and mice deficient in EBI2 mount diminished antibody responses. Very recently, oxidized metabolites of cholesterol were identified as EBI2 ligands, providing evidence of a new role for oxysterols in biology. This proposal will investigate the roles of EBI2 and oxysterols in the immune system by pursuing three specific aims. First, the mechanism of EBI2-mediated repositioning of activated B cells during antibody responses will be investigated. This will include an exploration of how EBI2-dependent niches augment the antibody response. Second, the role of key oxysterol biosynthetic and catabolic enzymes in generating EBI2 ligand gradients will be defined. The cellular distribution and regulation of enzyme activity in lymphoid tissues will be explored. The third aim will follow-up on evidence for high EBI2 ligand production in the lung during viral infection and examine the role of EBI2 in the B and T cell response to influenza virus infection. Finally, this proposal will follow-up on the recent genetic linkage that was found between tissue inflammation in spontaneous hypertensive rats and polymorphisms causing reduced EBI2 expression in macrophages. A genetic association was also detected between EBI2 polymorphisms and type I diabetes in humans. This longer-term effort will explore the hypothesis that EBI2 expression distinguishes macrophages with different inflammatory activity. Mounting appropriately regulated immune responses is essential for human health. This work will define how a newly characterized ligand-receptor system functions to promote antibody responses to vaccine antigens and it will examine the role it plays in the lung during the response to influenza virus. The research will also begin to unravel how this ligand-receptor system affects inflammatory gene expression during chronic tissue inflammation. PUBLIC HEALTH RELEVANCE: Mounting appropriately regulated immune responses is essential for human health. This work will define how a newly characterized ligand-receptor system, involving an oxysterol and a seven transmembrane receptor, functions to promote antibody responses to vaccine antigens and it will examine the role it plays in the lung during the response to influenza virus. The research will also begin to unravel how this ligand- receptor system affects inflammatory gene expression during chronic tissue inflammation.